Comprehensive review of thrombotic microangiopathy: classification, genetics, and management

Thrombotic microangiopathy (TMA) comprises syndromes characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ injury, most commonly affecting the kidneys and brain. Recent advances have reframed TMAs from classical clinical labels (thrombotic thrombocytopenic purpura [TTP], hemolytic uremic syndrome, secondary TMA) toward a pathway‑based view centered on complement dysregulation, severe ADAMTS13 deficiency, and secondary endothelial injury. This review integrates current data on genetics, environmental "triggers," and clinical presentation to support a two‑hit model in which germline or acquired susceptibility is unmasked by infection, pregnancy, drugs, transplantation, or malignant hypertension. Building on this framework, we propose a stepwise diagnostic approach that combines ADAMTS13 testing, targeted evaluation for secondary causes, and rational use of complement and genetic testing, with the goal of assigning each patient to a dominant pathogenic pathway. Finally, we discuss mechanism‑based treatment strategies-including plasma exchange and immunosuppression for ADAMTS13‑mediated TTP, complement inhibition for complement‑mediated TMA, and trigger‑directed management in secondary forms-and outline key uncertainties regarding treatment duration, relapse prediction, and access to advanced therapies.