Off the Beaten Path

Thrombotic microangiopathy (TMA) is a histopathological entity characterized by endothelial injury and microvascular thrombosis, clinically presenting with microangiopathic hemolytic anemia, thrombocytopenia, and organ dysfunction. TMA encompasses a heterogeneous group of disorders with overlapping clinical features, challenging consistent classification. Traditional designations such as typical hemolytic uremic syndrome (HUS), atypical HUS (aHUS), primary TMA and secondary TMA have often blurred the underlying mechanisms they were meant to distinguish. In recent years, complement-mediated TMA has garnered attention, largely because complement inhibition represents the only effective targeted therapy currently available. This therapeutic success has inadvertently led to a strong emphasis on complement activity in other TMAs, where complement activation is frequently detected but not necessarily causal and pivotal. This review focuses on non-complement mediated TMA, in particular those associated with coagulation dysregulation, VEGF deficiency, and direct endothelial injury. In these entities, complement activation typically represents a downstream consequence rather than the initiating event. Understanding the distinct molecular pathways underlying these forms is essential for accurate disease classification and rational therapeutic targeting.