TA-TMA as a clinical model for precision complement therapeutics in stem cell transplantation.

Abstract

Transplant-associated thrombotic microangiopathy (TA-TMA) has evolved from a poorly understood and frequently fatal complication of hematopoietic stem cell transplantation (HSCT) into the leading clinical model for precision complement therapeutics. Studies of TA-TMA have established endothelial injury and complement dysregulation as clinically actionable mechanisms and demonstrated that successful complement inhibition requires more than selecting an effective therapeutic agent. Longitudinal pharmacokinetic/pharmacodynamic (PK/PD)-guided dosing, durable terminal complement blockade, and integration of biomarkers reflecting complement activation, endothelial injury, inflammation, and organ dysfunction have transformed eculizumab into the first example of individualized complement-directed therapy in transplantation. Beyond improving outcomes in patients with TA-TMA, these advances have fundamentally changed our understanding of post-transplant endothelial injury, revealing shared biological pathways across multiple transplant-associated complications and supporting a transition from syndrome-based to mechanism-based clinical management. The expanding availability of eculizumab biosimilars and complement pathway-specific inhibitors, including lectin pathway inhibition, further broadens opportunities for personalized therapeutic strategies while emphasizing the need for harmonized diagnostic criteria, standardized response assessment, and biomarker-guided patient selection. Together, the lessons learned from TA-TMA provide a framework for future precision complement therapeutics in transplantation and illustrate how mechanistic understanding of disease biology can transform clinical practice.